PURPOSEIt was shown earlier by our group and others that sphingomyelinase (SMase) induces changes of vascular tone with an initial contraction and subsequent relaxation in aortic rings of wild type mice. Sphingolipids are essential components of cell membranes and sphingolipid metabolites have been implicated as important regulators in diabetes. Thus, we aimed to investigate the vascular effects of SMase in a mouse model of diabetes and to elucidate the involved potential mediators and signal transduction pathways.

RESULTSSMase evoked an initial contraction in control vessels (13.8±6.3%) followed by relaxation to the original tone, while it caused a marked relaxation in the diabetic vessels (-21.9±7.1%). L-NAME administration further increased the contraction in the control (25.3±7.6%) and contraction occured in the diabetic vessels as well (36.8±3.1%). SQ 29,548 led to relaxation in both groups, but these were more pronounced in the db/db group (-25.1±6.3% vs. -63.1±14.9%). Co-administration of the inhibitors caused no change in vascular tone after SMase treatment. The use of D-erythro-MAPP, Wortmannin and MK2206 did not alter the vasoactive effects of SMase in any group, but propargylglycin decreased the SMase induced vasorelaxation (-22.02±4.95%, p<0.05) in diabetic vessels.

CONCLUSIONSSMase induces biphasic changes in the tone of db/db mice derived vessels and these effects are mediated by thromboxane A2 and endothelial nitric oxide. Importantly, the relaxations are enhanced in diabetic vessels, which is a surprising and novel phenomenon. Our finding that CSE plays a profound role in these enhanced relaxations may provide a possible explanation to this. CSE produces hydrogen sulphide, a novel gasotransmitter that can inhibit phosphodiesterase in smooth muscles leading to higher levels of cGMP, thus relaxation. Our results may indicate a novel possibility to enhance vasorelaxation in diabetes by SMase via hydrogen sulphide signaling.